CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors

Xi, Meiyang; Chen, Tingkai; Wu, Chunlei; Gao, Xuechuan; Wu, Yeming; Luo, Xiang; Du, Kui; Yu, Le-Mao; Cai, Tao; Shen, Runpu; Sun, Haopeng

doi:10.1016/j.ejmech.2018.11.076

Cited by 52 publications

(38 citation statements)

References 98 publications

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“…The paralog kinases CDK8/19 were engaged by a number of CDKi's with nanomolar intracellular affinity. CDK8/19 are closely related but relatively understudied members of the CDK family that have been identified as components of the mediator complex involved in global regulation of transcription in eukaryotic cells 45 and are potential oncogenes in a subset of solid tumors 46 . Recently, two chemical probes have been described for CDK8/19 47,48 .…”

Section: (Supplementarymentioning

confidence: 99%

Quantifying CDK inhibitor selectivity in live cells

et al. 2020

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Concerted multidisciplinary efforts have led to the development of Cyclin-Dependent Kinase inhibitors (CDKi's) as small molecule drugs and chemical probes of intracellular CDK function. However, conflicting data has been reported on the inhibitory potency of CDKi's and a systematic characterization of affinity and selectivity against intracellular CDKs is lacking. We have developed a panel of cell-permeable energy transfer probes to quantify target occupancy for all 21 human CDKs in live cells, and present a comprehensive evaluation of intracellular isozyme potency and selectivity for a collection of 46 clinically-advanced CDKi's and tool molecules. We observed unexpected intracellular activity profiles for a number of CDKi's, offering avenues for repurposing of highly potent molecules as probes for previously unreported targets. Overall, we provide a broadly applicable method for evaluating the selectivity of CDK inhibitors in living cells, and present a refined set of tool molecules to study CDK function.

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Section: (Supplementarymentioning

confidence: 99%

Quantifying CDK inhibitor selectivity in live cells

et al. 2020

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“…As a subunit of the Mediator complex, CDK8 can either positively or negatively regulate gene transcription [ 15 , 33 ]. The oncogenic effects caused by gained CDK8 in melanoma and colorectal cancers have spurred an interest to develop CDK8-specific inhibitors for cancer treatment [ 7 , 32 , 34 , 35 , 36 ]. Thus we analyzed the specific interactions between hCDK8 and BAX, one of the CDK8 inhibitors [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

All-Atomic Molecular Dynamic Studies of Human and Drosophila CDK8: Insights into Their Kinase Domains, the LXXLL Motifs, and Drug Binding Site

Xie

Faust

et al. 2020

IJMS

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Cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC) play conserved roles in modulating RNA polymerase II (Pol II)-dependent gene expression. To understand the structure and function relations of CDK8, we analyzed the structures of human and Drosophila CDK8 proteins using molecular dynamics simulations, combined with functional analyses in Drosophila. Specifically, we evaluated the structural differences between hCDK8 and dCDK8 to predict the effects of the LXXLL motif mutation (AQKAA), the P154L mutations, and drug binding on local structures of the CDK8 proteins. First, we have observed that both the LXXLL motif and the kinase activity of CDK8 are required for the normal larval-to-pupal transition in Drosophila. Second, our molecular dynamic analyses have revealed that hCDK8 has higher hydrogen bond occupation of His149-Asp151 and Asp151-Asn156 than dCDK8. Third, the substructure of Asp282, Phe283, Arg285, Thr287 and Cys291 can distinguish human and Drosophila CDK8 structures. In addition, there are two hydrogen bonds in the LXXLL motif: a lower occupation between L312 and L315, and a relatively higher occupation between L312 and L316. Human CDK8 has higher hydrogen bond occupation between L312 and L316 than dCDK8. Moreover, L312, L315 and L316 in the LXXLL motif of CDK8 have the specific pattern of hydrogen bonds and geometries, which could be crucial for the binding to nuclear receptors. Furthermore, the P154L mutation dramatically decreases the hydrogen bond between L312 and L315 in hCDK8, but not in dCDK8. The mutations of P154L and AQKAA modestly alter the local structures around residues 154. Finally, we identified the inhibitor-induced conformational changes of hCDK8, and our results suggest a structural difference in the drug-binding site between hCDK8 and dCDK8. Taken together, these results provide the structural insights into the roles of the LXXLL motif and the kinase activity of CDK8 in vivo.

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“…CDK8 as an oncogene has been reported in various cancers, especially CRC [6,22], and it modulates over-activation of Wnt/β-catenin signalling pathway, which is one of the earliest events of tumourigenesis and progression [23]. Emerging evidence suggests that CDK8 may represent a promising target for cancer therapeutics via development of novel CDK8 inhibitors [23,24]. But the current situation is not so optimistic for pharmacological inhibition of CDK8 in cancer therapy, reflecting that CDK8 gene knockdown may have some advantages for inhibiting cancer cell proliferation [25].…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 8/β-catenin signalling contributes to tumourigenesis in prostate cancer and can be regulated by miR-216a-5p

Hong

et al. 2020

Arch Med Sci

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Introduction: Cyclin-dependent kinase 8 (CDK8), as an oncogene, contributes to carcinogenesis in several cancer types. However, the role of CDK8 in prostate cancer (PCa) has not been completely clarified. The present study was to investigate the molecular mechanisms underlying the progression of PCa. Material and methods: In human specimens, RT-qPCR and immunohistochemical (IHC) staining were used to detect the mRNA and protein expression of CDK8, respectively. In vitro experiments, MTT and colony formation assay, transwell assay, and Annexin V (FITC) double staining were performed to analyse cell proliferation, migration, invasion, and apoptosis, respectively. Results: Up-regulation of CDK8 was observed in PCa tissues and associated with poor overall survival (OS) and disease-free survival (DFS). Knockdown of CDK8 by shRNA was able to repress cell proliferation and induce cell apoptosis in PC3 and DU145 cells, as well as reduce the protein expression of Wnt/β-catenin pathway components. CDK8 was a direct target of miR-216a-5p, and overexpression of CDK8 reduced the antineoplastic activities of miR-216a-5p in vitro. Furthermore, miR-216a-5p could serve as an independent prognostic indicator for predicting the OS of PCa. Conclusions: miR-216a-5p/CDK8/β-catenin signalling cascade modulates the aggression of PCa. miR-216a-5p and CDK8, as promising therapeutic targets, might facilitate the development of therapeutic strategies for the treatment of PCa.

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CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors

Cited by 52 publications

References 98 publications

Quantifying CDK inhibitor selectivity in live cells

Quantifying CDK inhibitor selectivity in live cells

All-Atomic Molecular Dynamic Studies of Human and Drosophila CDK8: Insights into Their Kinase Domains, the LXXLL Motifs, and Drug Binding Site

Cyclin-dependent kinase 8/β-catenin signalling contributes to tumourigenesis in prostate cancer and can be regulated by miR-216a-5p

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